WO2022115526A1 - Treatment of public speaking anxiety with an alpha-7 nicotinic acetylcholine receptor agonist - Google Patents

Treatment of public speaking anxiety with an alpha-7 nicotinic acetylcholine receptor agonist Download PDF

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Publication number
WO2022115526A1
WO2022115526A1 PCT/US2021/060720 US2021060720W WO2022115526A1 WO 2022115526 A1 WO2022115526 A1 WO 2022115526A1 US 2021060720 W US2021060720 W US 2021060720W WO 2022115526 A1 WO2022115526 A1 WO 2022115526A1
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Prior art keywords
sad
individual
compound
symptom
fear
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PCT/US2021/060720
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English (en)
French (fr)
Inventor
Mihael Polymeropoulos
Yunsheng He
Christos POLYMEROPOULOS
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Vanda Pharmaceuticals Inc.
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Application filed by Vanda Pharmaceuticals Inc. filed Critical Vanda Pharmaceuticals Inc.
Priority to AU2021387993A priority Critical patent/AU2021387993A1/en
Priority to KR1020237016855A priority patent/KR20230112622A/ko
Priority to EP21827781.2A priority patent/EP4251158A1/en
Priority to CA3199760A priority patent/CA3199760A1/en
Priority to US18/249,920 priority patent/US20230381169A1/en
Priority to JP2023532250A priority patent/JP2023553354A/ja
Priority to CN202180078044.4A priority patent/CN116761604A/zh
Priority to MX2023005895A priority patent/MX2023005895A/es
Publication of WO2022115526A1 publication Critical patent/WO2022115526A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics

Definitions

  • the invention relates to a method for the treatment of public speaking anxiety (PSA), including public speaking anxiety as a presenting symptom of, or associated with social anxiety disorder (SAD) or social anxiety disorder-performance only subtype (SAD-PO).
  • PSA public speaking anxiety
  • SAD social anxiety disorder
  • SAD-PO social anxiety disorder-performance only subtype
  • the invention particularly relates to a method for the treatment of anxiety associated with public speaking or performance as described herein with an alpha 7 nicotinic acetylcholine receptor (a7 nAChR) agonist, particularly with (R)-3- (6-p-tolyl-pyridin-3-yloxy)-l-aza-bicyclo[2.2.2]octane.
  • a7 nAChR alpha 7 nicotinic acetylcholine receptor
  • PSA Public speaking anxiety
  • DSM-5 Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) (2013) as a social anxiety disorder (SAD).
  • SAD social anxiety disorder
  • the prevalence of PSA has been reported to be as high as 15% to 30% of the general population, with up to 10% of those with PSA reporting that the condition interferes with daily activities, including work and education.
  • Vickram Tejwani MD, et al., Public Speaking Anxiety in graduate Medical Education — A Matter of Interpersonal and Communication Skills?, Journal of graduate Medical Education, p. Ill (Feb. 01, 2016).
  • SAD Social anxiety disorder
  • PSA Public Safety Agent
  • SAD-PO Social anxiety disorder performance only
  • SAD-PO arises in narrower circumstances, namely, when a sufferer must perform in public. PSA and symptoms thereof may arise in individuals meeting the diagnostic criteria for SAD, for SAD-PO, for both SAD and SAD-PO, or for neither SAD nor SAD-PO.
  • the Public Speaking Anxiety Scale is used to assess the three- component model of anxiety.
  • the PSAS consists of seventeen items across three subscales: 1) cognitive (eight items), 2) behavioral (four items), and 3) physiological (five items). Each item has a score ranging from 1 (“not at all”) to 5 (“extremely”), with five items on the scale being reverse coded.
  • the PSAS total score can range from 17 to 85, and is considered a highly reliable and comprehensive measure to assess public speaking anxiety.
  • Symptoms of PSA, SAD, and SAD-PO may include physiological biomarkers associated with acute stress response, such as elevated heart rate, blood pressure, body temperature, or increased sweating, and other physical, cognitive, and emotional symptoms, e.g., shaking or trembling, blushing, rapid or difficulty breathing, dizziness, nausea, restlessness, muscle tension, sleep disturbances, excessive rumination or worry, difficulty concentrating outside of what is causing the anxiety, a feeling of the sufferer’s mind having gone blank, fear of judgment, fear of making a mistake, fear of embarrassment, fear of people looking at the sufferer, fear of certain situations, e.g., ordering at a restaurant or speaking in front of a crowd, engaging in negative self-talk, and other symptoms as known in the art.
  • physiological biomarkers associated with acute stress response such as elevated heart rate, blood pressure, body temperature, or increased sweating
  • other physical, cognitive, and emotional symptoms e.g., shaking or trembling, blushing, rapid or difficulty breathing, dizzi
  • SSRIs selective serotonin reuptake inhibitors
  • SNRI serotonin norepinephrine reuptake inhibitor
  • Other medications including monoamine oxidase inhibitors (MAOIs) and benzodiazepines (BZDs) have showed efficacy in placebo- controlled clinical trials with small sample sizes.
  • MAOIs monoamine oxidase inhibitors
  • BZDs benzodiazepines
  • the SSRIs increase synaptic serotonin levels and are considered as a first line treatment for SAD, but the onset of action is slow. Additionally, approximately 40% of patients treated with SSRIs report sexual dysfunction associated with SSRI use.
  • BZDs are gamma-aminobutyric acid (GABA)-positive allosteric modulators with adverse effects such as drowsiness, memory disturbances, sedation, and abuse liability. In addition, high rates of partial response and low rates of long-term remission remain.
  • GABA gamma-aminobutyric acid
  • the alpha-7 nicotinic acetylcholine receptor (a7-nAChR) is a ligand-gated ion channel and is involved in many physiologic and pathologic processes.
  • a unique feature of a7-nAChR is high Ca 2+ permeability and fast desensitization.
  • the a7- nAChR is highly expressed in the nervous system, especially in the regions implicated in cognition and memory, and its dysfunction is associated with several neuropsychiatric and neurological disorders including schizophrenia and Alzheimer’s disease (AD).
  • VQW-765 is a potent and selective a7 nAChR agonist disclosed in US Pat. 7,579,362.
  • the compound is also known as (R)-3-((6-(p-tolyl)pyri din-3 -yl)oxy)quinuclidine, AQW- 051, VQW-765, and by the IUPAC name, (3R)-3- ⁇ [6-(4-methylphenyl)pyridine-3- yl]oxy ⁇ -l- azabicyclo[2.2.2]octane.
  • VQW-765 has a molecular weight of 294.39 g/mol, a pKa (predicted) of 9.09 ⁇ 0.33, and aLogP (predicted) of 3.447 ⁇ 0.402.
  • Pharmaceutically acceptable acid addition salts of (R)-3-(6-p-Tolyl-pyridin-3-yloxy)- l-aza-bicyclo[2.2.2]octane, and particularly the mono-fumarate salt are disclosed in US Pat. 9,365,565.
  • VQW-765 as an a7 nAChR agonist useful for the prevention and treatment of psychotic disorders such as schizophrenia, mania, depression and anxiety, and for the prevention and treatment of neurodegenerative disorders such as senile dementia, Alzheimer’s disease and other intellectual impairment disorders, such as attention deficit hyperactivity disorders (ADHD); Parkinson’s disease, Huntington’s chorea, amyotrophic lateral sclerosis, multiple sclerosis, epilepsy, convulsions, Tourette syndrome, OCD (obsessive compulsive disorder), neuropathic, postoperative and inflammatory pain, phantom limb pain, cognition, smoking cessation, memory deficits and dysfunction, learning deficit, panic disorders, narcolepsy, nociception, AIDS dementia, senile dementia, autism, tardive dyskinesia, social phobia, pseudodementia.
  • ADHD attention deficit hyperactivity disorders
  • Parkinson’s disease Huntington’s chorea
  • amyotrophic lateral sclerosis multiple sclerosis
  • a first aspect of the disclosure provides a method of treatment of an individual suffering from public speaking anxiety or a symptom thereof, the method comprising: administering to the individual (R)-3-(6-p-tolyl-pyridin-3-yloxy)-l-aza- bicyclo[2.2.2]octane or a pharmaceutically acceptable salt thereof at a dose effective to treat the public speaking anxiety or the symptom thereof.
  • the individual may suffer from public speaking anxiety as a presenting symptom of social anxiety disorder (SAD) or SAD-performance only (SAD-PO), and may or may not have been diagnosed with SAD or SAD-PO.
  • SAD social anxiety disorder
  • SAD-PO SAD-performance only
  • a second aspect of the disclosure provides a method of treating social anxiety disorder (SAD) or a symptom thereof in an individual, the method comprising: administering to the individual (R)-3-(6-p-tolyl-pyridin-3-yloxy)-l-aza- bicyclo[2.2.2]octane or a pharmaceutically acceptable salt thereof at a dose effective to treat the SAD or the symptom thereof.
  • the individual may in certain embodiments suffer from social anxiety disorder-performance only subtype (SAD-PO), and may or may not have been diagnosed with SAD or SAD-PO.
  • a third aspect of the disclosure provides a method for preventing a manifestation of one or more symptoms of public speaking anxiety in an individual.
  • the method may comprise administering to the individual a compound prior to engaging in a situation such as, e.g., public speaking or public performance, that is likely to provoke or cause anxiety or one or more symptoms of anxiety.
  • the compound may be (R)-3-(6-p-tolyl-pyridin-3-yloxy)-l-aza- bicyclo[2.2.2]octane or a pharmaceutically acceptable salt thereof, and it may be administered at a dose effective to prevent such a manifestation.
  • a fourth aspect of the disclosure provides a compound that is (R)-3-(6-p-tolyl- pyridin-3-yloxy)-l-aza-bicyclo[2.2.2]octane or a pharmaceutically acceptable salt thereof, for use in the treatment of public speaking anxiety or a symptom thereof.
  • the individual may suffer from public speaking anxiety as a presenting symptom of social anxiety disorder (SAD) or SAD-performance only (SAD-PO), and may or may not have been diagnosed with SAD or SAD-PO.
  • SAD social anxiety disorder
  • SAD-PO SAD-performance only
  • a fifth aspect of the disclosure provides a compound that is (R)-3-(6-p-tolyl- pyridin-3-yloxy)-l-aza-bicyclo[2.2.2]octane or a pharmaceutically acceptable salt thereof, for use in the treatment of social anxiety disorder (SAD) or a symptom thereof.
  • the individual may in certain embodiments suffer from social anxiety disorder-performance only subtype (SAD-PO), and may or may not have been diagnosed with SAD or SAD-PO.
  • a sixth aspect of the disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound that is (R)-3-(6-p-tolyl-pyridin-3-yloxy)-l-aza- bicyclo[2.2.2]octane or a pharmaceutically acceptable salt thereof for use in the treatment of public speaking anxiety or a symptom thereof.
  • the individual may suffer from public speaking anxiety as a presenting symptom of social anxiety disorder (SAD) or SAD-performance only (SAD-PO), and may or may not have been diagnosed with SAD or SAD-PO.
  • SAD social anxiety disorder
  • SAD-PO SAD-performance only
  • a seventh aspect of the disclosure provides a pharmaceutical composition that is (R)-3-(6-p-tolyl-pyridin-3-yloxy)-l-aza-bicyclo[2.2.2]octane or a pharmaceutically acceptable salt thereof, for use in the treatment of social anxiety disorder or a symptom thereof.
  • the individual may in certain embodiments suffer from social anxiety disorder-performance only subtype (SAD-PO), and may or may not have been diagnosed with SAD or SAD-PO.
  • SAD-PO social anxiety disorder-performance only subtype
  • An eighth aspect of the disclosure provides a compound that is (R)-3-(6-p- tolyl-pyridin-3-yloxy)-l-aza-bicyclo[2.2.2]octane or a pharmaceutically acceptable salt thereof for use in the manufacture of a pharmaceutical composition comprising the compound for use in the treatment of public speaking anxiety.
  • the individual may suffer from public speaking anxiety as a presenting symptom of social anxiety disorder (SAD) or SAD-performance only (SAD-PO), and may or may not have been diagnosed with SAD or SAD-PO.
  • SAD social anxiety disorder
  • SAD-PO SAD-performance only
  • a ninth aspect of the disclosure provides a compound that is (R)-3-(6-p-tolyl- pyridin-3-yloxy)-l-aza-bicyclo[2.2.2]octane or a pharmaceutically acceptable salt thereof for use in the manufacture of a pharmaceutical composition comprising the compound for use in the treatment of social anxiety disorder (SAD).
  • SAD social anxiety disorder
  • the individual may in certain embodiments suffer from social anxiety disorder-performance only subtype (SAD-PO), and may or may not have been diagnosed with SAD or SAD-PO.
  • the methods described herein include methods for the treatment of an individual suffering from public speaking anxiety, an individual suffering from social anxiety disorder (SAD) or at least one symptom thereof, or an individual suffering from the performance only subtype of social anxiety disorder (SAD-PO). Such individuals may experience performance or public speaking anxiety as a presenting symptom.
  • SAD social anxiety disorder
  • SAD-PO performance only subtype of social anxiety disorder
  • references to an individual suffering from social anxiety disorder may be considered to include individuals meeting diagnostic criteria for social anxiety disorder (SAD) as understood by those skilled in the art.
  • SAD social anxiety disorder
  • Such individuals may meet the diagnostic criteria for social anxiety disorder set forth in the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5), pp. 202-208 (2013).
  • DSM-5 Diagnostic and Statistical Manual of Mental Disorders, 5th edition
  • references to an individual suffering from social anxiety disorder- performance only may be considered to include individuals meeting diagnostic criteria for the SAD-PO subtype as understood by those skilled in the art. For example, such individuals may meet the diagnostic criteria for the social anxiety disorder-performance only specifier as set forth in the DSM-5. Such references are considered to include both individuals diagnosed with SAD-PO, and those who may meet the diagnostic criteria but have not been diagnosed for any number of reasons including, e.g., not having presented for clinical care for SAD-PO or symptoms thereof.
  • references to an individual suffering from public speaking anxiety may include individuals who experience symptoms of anxiety associated with public speaking or performance.
  • Such anxiety may be referred to as “stage fright,” and may be brought on by any of a number of types of public performance, for example, musical performance, athletic performance, acting performances, and public speaking, or anticipation of such public performance.
  • Such individuals may meet many to all of the diagnostic criteria for SAD, including, e.g., marked anxiety or fear about performing in front of others (e.g., giving a speech).
  • Individuals suffering from PSA may include individuals who are not diagnosed with SAD, but who nonetheless experience PSA.
  • PSA Public Speaking Anxiety Scale
  • references to treatment of an individual with one or more of PSA, SAD, or SAD-PO may be considered to include a reduction in severity of the individual’s symptoms, prevention or attenuation of progression of PSA, SAD, or SAD-PO in the individual, prevention or attenuation of the individual’s symptoms in response to a situation or stimulus, or complete resolution of one or more of the individual’s symptoms of PSA, SAD, or SAD-PO after such symptom or symptoms have become manifest in the individual.
  • a method for the treatment of an individual suffering from PSA, suffering from SAD, suffering from SAD-PO, or suffering from one or more symptoms of any of the foregoing.
  • Such individual may or may not have been formally diagnosed with any of the foregoing conditions.
  • this may include an individual suffering from public speaking anxiety or public performance anxiety.
  • the method includes the process of administering to the individual a compound that is (R)-3-(6-p-tolyl-pyridin-3-yloxy)-l-aza- bicyclo[2.2.2]octane or a pharmaceutically acceptable salt thereof in an amount, i.e. at a dose effective to produce the desired therapeutic response.
  • the compound may be ⁇ 2-(R)-3-[[6-(4-Methylphenyl)-3-pyridinyl]oxy]-l- azabi cy cl o [2.2.2] octane fumarate .
  • a dose effective to produce the desired therapeutic response is an amount or dosage that is effective to treat the symptoms or underlying PSA, SAD, or SAD-PO in the individual, to shorten the course or lessen the severity of the manifestation of the condition or disorder, or to prevent, mitigate, or ameliorate symptoms of the condition or disorder.
  • the dose for a human may be an amount between about 0.5 mg and about 700 mg as described in Table 1, e.g., about 0.5 mg, about 2 mg, about 2.5 mg, about 10 mg, about 15 mg, about 75 mg, about 100 mg, about 200 mg, or about 700 mg.
  • the dose of the active agent of the present invention may be varied so as to administer an amount of the active agent which is effective to achieve the desired therapeutic response for a particular individual without being toxic to the individual.
  • the selected dosage will depend upon a variety of pharmacokinetic factors including the route of administration, the time of administration, the rate of excretion, the duration of the treatment, other drugs, compounds, or materials used in combination with the particular compositions employed, the age, sex, weight, condition, general health and prior medical history of the individual being treated, and like factors well known in the medical arts.
  • a method for treating PSA, SAD, SAD- PO, or at least one symptom thereof in an individual by administering to the individual a compound that is (R)-3-(6-p-tolyl-pyridin-3-yloxy)-l-aza- bicyclo[2.2.2]octane or a pharmaceutically acceptable salt thereof.
  • the compound may be administered at a dosage described herein as one that is therapeutically effective.
  • a method of treatment including administering a compound that is (R)-3-(6-p-tolyl-pyridin-3-yloxy)-l-aza- bicyclo[2.2.2]octane or a pharmaceutically acceptable salt thereof to a human individual suffering from PSA, SAD, or SAD-PO, or symptoms of one of the foregoing.
  • the individual may or may not have been formally diagnosed with SAD or SAD-PO.
  • the compound is administered in a therapeutically effective amount, i.e., an amount sufficient to relieve the at least one symptom of SAD or SAD-PO.
  • Such symptoms of PSA, SAD, and SAD-PO may include physical, cognitive, and emotional symptoms, e.g., shaking or trembling, blushing, increased heart rate, blood pressure, body temperature, or sweating, rapid or difficulty breathing, dizziness, nausea, restlessness, muscle tension, sleep disturbances, excessive rumination or worry, difficulty concentrating outside of what is causing the anxiety, a feeling of the sufferer’s mind having gone blank, fear of judgment, fear of making a mistake, fear of embarrassment, fear of people looking at the sufferer, fear of certain situations, e.g., ordering at a restaurant or speaking in front of a crowd, engaging in negative self-talk, and other symptoms as known in the art.
  • physical, cognitive, and emotional symptoms e.g., shaking or trembling, blushing, increased heart rate, blood pressure, body temperature, or sweating, rapid or difficulty breathing, dizziness, nausea, restlessness, muscle tension, sleep disturbances, excessive rumination or worry, difficulty concentrating outside of what is
  • the emotional, cognitive, and physical symptoms may also be considered to include behavior alterations including refusing invitations, clinging to familiar people in group situations, and avoiding the situations, events, or circumstances that cause them anxiety, as well as unhealthy coping mechanism such as use of alcohol or drugs.
  • a method for preventing an acute manifestation of one or more symptom of PSA, SAD, or SAD-PO in an individual.
  • Prevention in this context may include prevention in whole or in part, such as a reduction in severity.
  • the method includes administering to the individual a compound that is (R)-3-(6-p-tolyl-pyridin-3-yloxy)-l-aza- bicyclo[2.2.2]octane or a pharmaceutically acceptable salt thereof, prior to engaging in a situation likely to provoke anxiety, e.g., prior to participating in a public speaking engagement, and in an amount effective to prevent the symptom(s).
  • the situation likely to provoke anxiety may be, e.g., performing in front of one or more other people, or public speaking
  • the symptom of SAD or particularly of SAD-PO whose manifestation is to be prevented may be, e.g., shaking or trembling, blushing, increased heart rate, rapid or difficulty breathing, dizziness, nausea, restlessness, sweating, muscle tension, sleep disturbances, excessive rumination or worry, difficulty concentrating outside of what is causing the anxiety, a feeling of the sufferer’s mind having gone blank, fear of judgment, fear of making a mistake, fear of embarrassment, fear of people looking at the sufferer, fear of certain situations, e.g., ordering at a restaurant or speaking in front of a crowd, and engaging in negative self-talk.
  • the compound may be (R)-3-(6-p-tolyl- pyridin-3-yloxy)-l-aza-bicyclo[2.2.2]octane either in free base form or in a pharmaceutically acceptable acid addition salt form.
  • a pharmaceutically acceptable salt as used herein refers to a salt of a free form that is not toxic, biologically intolerable, or otherwise biologically undesirable.
  • Preferred pharmaceutically acceptable salts are those that are pharmacologically effective and suitable for contact with the tissues of individuals without undue toxicity, irritation, or allergic response.
  • Particularly preferred pharmaceutically acceptable acid addition salts of the present compound are described in US Pat.
  • the compound may be (R)-3-(6-p-tolyl-pyridin-3-yloxy)-l-aza-bicyclo[2.2.2]octane in mono-fumarate acid addition salt form, i.e. ⁇ 2-(R)-3-[[6-(4-Methylphenyl)-3- pyridinyl]oxy]-l-azabicyclo[2.2.2]octane fumarate.
  • the compound of the present invention can be administered by one or more routes of administration using one or more of a variety of methods known in the art.
  • routes of administration may include intravenous, intramuscular, intradermal, intraperitoneal, subcutaneous, spinal or other parenteral routes of administration, for example by injection or infusion.
  • parenteral administration means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrastemal injection and infusion.
  • compositions can be administered by a nonparenteral route, such as a topical, epidermal or mucosal route of administration, for example, intranasally, orally, vaginally, rectally, sublingually or topically.
  • a nonparenteral route such as a topical, epidermal or mucosal route of administration, for example, intranasally, orally, vaginally, rectally, sublingually or topically.
  • the active compounds can be prepared as a solid, immediate release form comprising the compound and one or more pharmaceutically acceptable excipients.
  • the active compounds can be prepared with carriers that will protect the compound against rapid release, such as a controlled release formulation, including implants, transdermal patches, and microencapsulated delivery systems.
  • a controlled release formulation including implants, transdermal patches, and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Many methods for the preparation of such formulations are patented or generally known to those skilled in the art.
  • compositions for oral or transdermal administration are compositions for oral or transdermal administration.
  • a composition for enteral or parenteral administration is, for example, a unit dosage form, such as a sugar-coated tablet, a tablet, a capsule, a suppository or an ampoule.
  • the unit content of active ingredients in an individual dose need not in itself constitute a therapeutically effective amount, since such an amount can be reached by the administration of a plurality of dosage units.
  • a composition according to the invention may contain, e.g., from about 10% to about 100%, preferably from about 20% to about 60%, of the active ingredients.
  • a pharmaceutical composition according to the invention is prepared in a manner known per se, e.g. by means of conventional mixing, granulating, sugar-coating, dissolving or lyophilizing processes.
  • any of the usual pharmaceutical media may be employed, for example water, glycols, oils, alcohols, carriers, such as starches, sugars, or microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid pharmaceutical carriers are obviously employed.
  • the compound may be orally administered in a solid immediate release form, e.g., a tablet or a capsule, comprising VQW-765 in an amount of, e.g., about 0.5 mg, about 2 mg, about 2.5 mg, about 10 mg, about 15 mg, about 75 mg, about 100 mg, about 200 mg, or about 700 mg of the compound, together with one or more pharmaceutically acceptable excipients.
  • a solid immediate release form e.g., a tablet or a capsule
  • VQW-765 in an amount of, e.g., about 0.5 mg, about 2 mg, about 2.5 mg, about 10 mg, about 15 mg, about 75 mg, about 100 mg, about 200 mg, or about 700 mg of the compound, together with one or more pharmaceutically acceptable excipients.
  • the compound may be orally administered in a solid controlled release form comprising the compound and one or more pharmaceutically acceptable excipients. Controlled release forms may contain larger doses with lower bioavailability as compared to immediate release forms.
  • the compound may be orally administered in a liquid suspension form, or intravenously administered in a liquid suspension form in a daily dosage providing comparable exposure to the compound.
  • a compound is (R)-3-(6-p-tolyl-pyridin-3- yloxy)-l-aza-bicyclo[2.2.2]octane or a pharmaceutically acceptable salt thereof, for use in any of the methods of treatment described herein.
  • a pharmaceutical composition comprising a compound that is (R)-3-(6-p-tolyl-pyridin- 3-yloxy)-l-aza-bicyclo[2.2.2]octane or a pharmaceutically acceptable salt thereof for use in any of the methods described herein.
  • a compound is provided that is (R)-3-(6-p-tolyl-pyridin-3- yloxy)-l-aza-bicyclo[2.2.2]octane or a pharmaceutically acceptable salt thereof for use in the manufacture of a pharmaceutical composition comprising the compound for use in any of the methods described herein.
  • Example 1 Social Anxiety Disorder Performance Only (SAD-PO); single dose
  • a multicenter, randomized, double-blind, placebo-controlled study is performed to evaluate the efficacy and safety of VQW-765 in patients with substantial public speaking anxiety according to the design in Table 2.
  • 220 patients are randomized to one of two arms in a 1 : 1 ratio.
  • Patients in one arm receive capsules containing 10 mg VQW-765 ( ⁇ 2-(R)-3-[[6-(4-Methylphenyl)-3-pyridinyl]oxy]-l- azabicyclo[2.2.2]octane fumarate), while patients in the other arm receive placebo.
  • VQW-765 capsules are size 3, white opaque, hard gelatin capsules provided as a strength of 10 mg, also containing lactose monohydrate, microcrystalline cellulose, methocel, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate. Placebo capsules are provided in size and appearance identical to those containing VQW-765. Table 2: Clinical trial design
  • Treatment VQW or placebo is given 2 hours prior to a TS ST
  • the Public Speaking Anxiety Scale (PSAS) is used to determine patients with substantial public speaking anxiety, defined as having a PSAS score greater than or equal to 60.
  • Clinical and laboratory assessments are performed to assess each patient’s eligibility. Eligible patients are trained on using a self-rated Subjective Units of Distress Scale (SUDS).
  • SUDS Subjective Units of Distress Scale
  • LSAS Liebowitz Social Anxiety Score
  • LSAS is a clinician-administered rating scale used to assess how social anxiety plays a role in daily life across a variety of situations.
  • the LSAS is used to study outcomes in clinical trials, and includes 24 items to assess both social anxiety in situations and avoidance of those situations. Each item is rated as 0, none; 1, mild; 2, moderate; or 3, severe.
  • the maximal score is 144.
  • TSST Trier Social Stress Test
  • Patients are given a single dose of 10 mg VQW-765 or placebo capsule. Two hours later, the patient is instructed to prepare for a 5-minute speech for a job interview, and is asked for a SUDS rating (resting phase). Then the patient has 3 minutes to mentally prepare. SUDS rating is collected at each minute (anticipation phase). Next, the patient gives a 5-minute speech to an audience of two clinical staff dressed in white coats and previously unknown to the patient. SUDS rating is collected just before the speech and then at each minute during the speech (performance phase). The speech is video recorded, and the video camera is observed by the patient.
  • Physiological biomarkers associated with anxiety or acute stress response including heart rate, blood pressure, body temperature, and sweating are monitored continuously by medical devices throughout the Public Speaking challenge.
  • CGI-C Clinician Global Impression - Change
  • PGI-C Patient Global Impression - Change
  • ECG electrocardiogram
  • the planned sample size of 110 patients per arm provides around 85% power to detect a mean difference of 12 points in the average of SUDS score assuming a standard deviation of 28 in each treatment group.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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PCT/US2021/060720 2020-11-25 2021-11-24 Treatment of public speaking anxiety with an alpha-7 nicotinic acetylcholine receptor agonist WO2022115526A1 (en)

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AU2021387993A AU2021387993A1 (en) 2020-11-25 2021-11-24 Treatment of public speaking anxiety with an alpha-7 nicotinic acetylcholine receptor agonist
KR1020237016855A KR20230112622A (ko) 2020-11-25 2021-11-24 알파-7 니코틴성 아세틸콜린 수용체 작용제를 사용한 대중 발표 불안증의 치료
EP21827781.2A EP4251158A1 (en) 2020-11-25 2021-11-24 Treatment of public speaking anxiety with an alpha-7 nicotinic acetylcholine receptor agonist
CA3199760A CA3199760A1 (en) 2020-11-25 2021-11-24 Treatment of public speaking anxiety with an alpha-7 nicotinic acetylcholine receptor agonist
US18/249,920 US20230381169A1 (en) 2020-11-25 2021-11-24 Treatment of public speaking anxiety with an alpha-7 nicotinic acetylcholine receptor agonist
JP2023532250A JP2023553354A (ja) 2020-11-25 2021-11-24 アルファ－７ニコチン性アセチルコリン受容体アゴニストを用いた、スピーチ不安の治療
CN202180078044.4A CN116761604A (zh) 2020-11-25 2021-11-24 用α-7烟碱型乙酰胆碱受体激动剂治疗当众讲话焦虑
MX2023005895A MX2023005895A (es) 2020-11-25 2021-11-24 Tratamiento de la ansiedad al hablar en publico con un agonista del receptor nicotinico alfa 7 de la acetilcolina.

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Citations (4)

* Cited by examiner, † Cited by third party
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WO2006048294A1 (en) * 2004-11-05 2006-05-11 Novartis Ag Combinations of nicotinic acetylcholine alpha 7 receptor agonists
US7579362B2 (en) 2002-09-04 2009-08-25 Novartis Ag Aza-bicycloalkyl ethers and their use as alpha7-nAChR agonists
EP2742940A1 (en) * 2012-12-13 2014-06-18 IP Gesellschaft für Management mbH Salts of aza-bicyclo-di-aryl ethers for adminstration once daily, twice daily or thrice daily
US9365565B2 (en) 2011-07-15 2016-06-14 Novartis Ag Salts of aza-bicyclic di-aryl ethers and pharmaceuticals thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7579362B2 (en) 2002-09-04 2009-08-25 Novartis Ag Aza-bicycloalkyl ethers and their use as alpha7-nAChR agonists
WO2006048294A1 (en) * 2004-11-05 2006-05-11 Novartis Ag Combinations of nicotinic acetylcholine alpha 7 receptor agonists
US9365565B2 (en) 2011-07-15 2016-06-14 Novartis Ag Salts of aza-bicyclic di-aryl ethers and pharmaceuticals thereof
EP2742940A1 (en) * 2012-12-13 2014-06-18 IP Gesellschaft für Management mbH Salts of aza-bicyclo-di-aryl ethers for adminstration once daily, twice daily or thrice daily

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CA3199760A1 (en) 2022-06-02
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